RRM2
Ribonucleoside-diphosphate reductase subunit M2 (EC 1.17.4.1) (Ribonucleotide reductase small chain) (Ribonucleotide reductase small subunit) [RR2]
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In Saccharomyces cerevisiae, absence of the checkpoint kinase Mec1 (ATR) is viable upon mutations that increase the activity of the ribonucleotide reductase (RNR) complex. Whether this pathway is conserved in mammals remains unknown. Here we show that cells from mice carrying extra alleles of the RNR regulatory subunit RRM2 (Rrm2(TG)) present supraphysiological RNR activity and reduced chromosomal breakage at fragile sites. Moreover, increased Rrm2 gene dosage significantly extends the life span of ATR mutant mice. Our study reveals the first genetic condition in mammals that reduces fragile site expression and alleviates the severity of a progeroid disease by increasing RNR activity.
MeSH Terms
- Animals
- Cell Line
- Cell Survival
- Cells, Cultured
- Chromosome Breakage
- Chromosome Fragile Sites
- Enzyme Activation
- Fibroblasts
- Gene Dosage
- Humans
- Longevity
- Mice
- Nucleosides
- Protein-Serine-Threonine Kinases
- Ribonucleoside Diphosphate Reductase
- Survival Analysis
Keywords
- ATR
- RNR
- fragile site
- mouse models
- replication stress
Epithelial ovarian cancer (EOC) is the leading cause of gynecological-related cancer deaths in the United States. There is, therefore, an urgent need to develop novel therapeutic strategies for this devastating disease. Cellular senescence is a state of stable cell growth arrest that acts as an important tumor suppression mechanism. Ribonucleotide reductase M2 (RRM2) plays a key role in regulating the senescence-associated cell growth arrest by controlling biogenesis of 2'-deoxyribonucleoside 5'-triphosphates (dNTPs). The role of RRM2 in EOC remains poorly understood. Here we show that RRM2 is expressed at higher levels in EOCs compared with either normal ovarian surface epithelium (P<0.001) or fallopian tube epithelium (P<0.001). RRM2 expression significantly correlates with the expression of Ki67, a marker of cell proliferation (P<0.001). Moreover, RRM2 expression positively correlates with tumor grade and stage, and high RRM2 expression independently predicts a shorter overall survival in EOC patients (P<0.001). To delineate the functional role of RRM2 in EOC, we knocked down RRM2 expression in a panel of EOC cell lines. Knockdown of RRM2 expression inhibits the growth of human EOC cells. Mechanistically, RRM2 knockdown triggers cellular senescence in these cells. Notably, this correlates with the induction of the DNA damage response, a known mediator of cellular senescence. These data suggest that targeting RRM2 in EOCs by suppressing its activity is a novel pro-senescence therapeutic strategy that has the potential to improve survival of EOC patients.
MeSH Terms
- Carcinoma, Ovarian Epithelial
- Cell Line, Tumor
- Cell Proliferation
- Cellular Senescence
- DNA Damage
- Epithelium
- Fallopian Tubes
- Female
- Gene Knockdown Techniques
- Humans
- Ki-67 Antigen
- Middle Aged
- Molecular Targeted Therapy
- Neoplasm Grading
- Neoplasm Staging
- Neoplasms, Glandular and Epithelial
- Ovarian Neoplasms
- Ovary
- Ribonucleoside Diphosphate Reductase
- Survival Rate
Keywords
- DNA damage response
- cell proliferation
- cellular senescence
- epithelial ovarian cancer
- ribonucleotide reductase M2 (RRM2)
Breast cancer in young women is more aggressive with a poorer prognosis and overall survival compared to older women diagnosed with the disease. Despite recent research, the underlying biology and molecular alterations that drive the aggressive nature of breast tumors associated with breast cancer in young women have yet to be elucidated. In this study, we performed transcriptomic profile and network analyses of breast tumors arising in Middle Eastern women to identify age-specific gene signatures. Moreover, we studied molecular alterations associated with cancer progression in young women using cross-species comparative genomics approach coupled with copy number alterations (CNA) associated with breast cancers from independent studies. We identified 63 genes specific to tumors in young women that showed alterations distinct from two age cohorts of older women. The network analyses revealed potential critical regulatory roles for Myc, PI3K/Akt, NF-κB, and IL-1 in disease characteristics of breast tumors arising in young women. Cross-species comparative genomics analysis of progression from pre-invasive ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC) revealed 16 genes with concomitant genomic alterations, CCNB2, UBE2C, TOP2A, CEP55, TPX2, BIRC5, KIAA0101, SHCBP1, UBE2T, PTTG1, NUSAP1, DEPDC1, HELLS, CCNB1, KIF4A, and RRM2, that may be involved in tumorigenesis and in the processes of invasion and progression of disease. Array findings were validated using qRT-PCR, immunohistochemistry, and extensive in silico analyses of independently performed microarray datasets. To our knowledge, this study provides the first comprehensive genomic analysis of breast cancer in Middle Eastern women in age-specific cohorts and potential markers for cancer progression in young women. Our data demonstrate that cancer appearing in young women contain distinct biological characteristics and deregulated signaling pathways. Moreover, our integrative genomic and cross-species analysis may provide robust biomarkers for the detection of disease progression in young women, and lead to more effective treatment strategies.
MeSH Terms
- Adult
- Aging
- Animals
- Biomarkers, Tumor
- Breast Neoplasms
- Carcinogenesis
- Carcinoma, Ductal, Breast
- Carcinoma, Intraductal, Noninfiltrating
- Cohort Studies
- Computational Biology
- Disease Progression
- Female
- Gene Expression Regulation, Neoplastic
- Gene Regulatory Networks
- Genes, Neoplasm
- Genome, Human
- Humans
- Immunohistochemistry
- Mice
- Middle Aged
- Oligonucleotide Array Sequence Analysis
- Reproducibility of Results
- Species Specificity
- Transcriptome
- Young Adult